FDA Grants Accelerated Approval for SIRTURO™ (bedaquiline) as Part of Combination Therapy to Treat Adults with Pulmonary Multi-Drug Resistant Tuberculosis

TITUSVILLE, N.J., Dec. 31, 2012 /PRNewswire/ -- Janssen Therapeutics, Division of Janssen Products, LP, today announced the U.S. Food and Drug Administration (FDA) has granted accelerated approval to SIRTURO™ (bedaquiline) Tablets for the treatment of pulmonary multi-drug resistant tuberculosis (MDR-TB) as part of combination therapy in adults. The accelerated approval is based on the surrogate endpoint of time to sputum culture conversion.

"SIRTURO™ was first discovered in our laboratories more than a decade ago and it is gratifying to see our discovery and development lead to the accelerated approval of the first TB therapy in 40 years with a new mechanism of action. This underscores our commitment as a company to discover, develop and responsibly deliver innovative medicines that address serious unmet medical needs," said Paul Stoffels, M.D., Chief Scientific Officer and Worldwide Chairman, Pharmaceuticals, Johnson & Johnson.

SIRTURO™ inhibits mycobacterial ATP (adenosine 5'‑triphosphate) synthase, an enzyme that is essential for the generation of energy in Mycobacterium tuberculosis.

SIRTURO™ is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in adults (greater than or equal to 18 years) with pulmonary MDR-TB. Reserve SIRTURO™ for use when an effective treatment regimen cannot otherwise be provided. SIRTURO™ should be administered by directly observed therapy (DOT). This indication is based on analysis of time to sputum culture conversion from two controlled Phase 2 trials in patients with pulmonary MDR-TB. The safety and efficacy of SIRTURO™ for the treatment of latent infection due to Mycobacterium tuberculosis has not been established. The safety and efficacy of SIRTURO™ for the treatment of drug-sensitive TB has not been established. In addition, there are no data on the treatment with SIRTURO™ of extra-pulmonary TB (e.g., central nervous system). Therefore, use of SIRTURO™ in these settings is not recommended.

The prescribing information for SIRTURO™ includes Boxed Warnings regarding increased risk of death and occurrence of QT prolongation. The Warnings and Precautions section provides additional information regarding these risks and includes risk of hepatic-related adverse drug reactions, drug interactions, use in HIV-TB co-infected patients and treatment failure. The most common adverse drug reactions were nausea, arthralgia and headache. Additional adverse events were hemoptysis and chest pain. Please see Important Safety Information below for more details.

MDR-TB is considered an orphan disease in the U.S., with 98 reported patients in 2011. MDR-TB is characterized by resistance to two of the most powerful medicines in today's four-drug standard TB treatment regimen. MDR-TB treatment is complex and requires up to two years of treatment with companion drugs in accordance with national TB treatment guidelines and local MDR-TB treatment practice, along with extensive medical supervision. The World Health Organization (WHO) estimates more than two million people will develop MDR-TB between 2011 and 2015.

"The accelerated approval of SIRTURO™ is a significant step in the fight against MDR-TB, which is a more difficult to treat form of TB that affects approximately 630,000 people in the world and is on the rise in many areas worldwide," said Dr. Stoffels.

"This is the first time a new drug is being introduced specifically for MDR-TB, for which the current needs are so great," said Lee Reichman, M.D., Executive Director, New Jersey Medical School Global Tuberculosis Institute. "It is an important step in the development of new compounds for this serious and contagious disease."

The FDA accelerated approval of SIRTURO™ was based on data from TMC207-C208 Study 1 and Study 2. The primary endpoint was time to sputum culture conversion, defined as the interval in days between the first dose of study drug and the date of the first of two consecutive negative sputum cultures collected at least 25 days apart during treatment.

TMC207-C208 Study 1 is a placebo-controlled, double-blind, randomized trial conducted in newly diagnosed patients with multi-drug resistant pulmonary Mycobacterium tuberculosis. Patients were randomized to receive treatment with either SIRTURO™ and other drugs used to treat MDR-TB (SIRTURO™ treatment group) (n=79) or placebo plus other drugs to treat MDR-TB (placebo treatment group) (n=81): the other drugs used to treat MDR-TB consisted of a combination of five other antimycobacterial drugs (ethionamide, kanamycin, pyrazinamide, ofloxacin, and cycloserine/terizidone or available alternative). SIRTURO™ was administered as 400 mg once daily for the first two weeks and as 200 mg three times per week for the following 22 weeks. After the 24 week study drug (SIRTURO™ or placebo) treatment phase patients continued to receive their other drugs used to treat MDR-TB until a total treatment duration of 18 to 24 months was achieved, or at least 12 months after the first confirmed negative culture.

The SIRTURO™treatment group had decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at week 24. Median time to culture conversion was 83 days for the SIRTURO™ treatment group, compared to 125 days for the placebo treatment group.

At week 24, culture conversation status results were:

77.6 percent of patients in the SIRTURO™ treatment group reached treatment success vs. 57.6 percent of patients in the placebo treatment group (p=0.014).

22.4 percent of patients in the SIRTURO™ treatment group experienced treatment failure vs. 42.4 percent of patients in the placebo treatment group.

7.5 percent of patients in the SIRTURO™ treatment group vs. 24.2 percent in the placebo treatment group experienced lack of conversion.

TMC207-C208 Study 2 is a smaller, placebo-controlled study designed similarly to Study 1 except that SIRTURO™ or placebo was given for only 8 weeks instead of 24 weeks. Patients were randomized to either SIRTURO™ and other drugs used to treat MDR-TB (SIRTURO™ treatment group) (n=23) or placebo and other drugs used to treat MDR-TB (placebo treatment group) (n=24). Twenty-one patients randomized to the SIRTURO™ treatment group and 23 patients randomized to the placebo treatment group had confirmed MDR-TB based on subjects' baseline M. tuberculosis isolate obtained prior to randomization. The SIRTURO™ treatment group had a decreased time to culture conversion and improved culture conversion rates compared to the placebo treatment group at week 8. At weeks 8 and 24, the differences in culture conversion proportions were 38.9 percent and 15.7 percent, respectively.

Important Safety Information

WARNINGS:

An increased risk of death was seen in the SIRTURO™ treatment group (9/79, 11.4%) compared to the placebo treatment group (2/81, 2.5%) in one placebo-controlled trial. Only use SIRTURO™ when an effective treatment regimen cannot otherwise be provided.

QT prolongation can occur with SIRTURO™. Use with drugs that prolong the QT interval may cause additive QT prolongation.

Warnings and Precautions

Increased Mortality: An increased risk of death was seen in the SIRTURO™ treatment group.

QT Prolongation: SIRTURO™ prolongs the QT interval. An electrocardiogram (ECG) should be obtained before initiation of treatment, and at least 2, 12 and 24 weeks after starting treatment with SIRTURO™. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Discontinue SIRTURO™ and all other QT prolonging drugs if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of > 500 ms (confirmed by repeat ECG).

The following may increase the risk for QT prolongation when patients are receiving SIRTURO™ and therefore ECGs should be monitored closely: use with other QT prolonging drugs including fluoroquinolones and macrolide antibacterial drugs and the antimycobacterial drug, clofazimine; a history of Torsade de Pointes; a history of cogenital long QT syndrome; a history of hypothyroidism and bradyarrhythmias; a history of uncompensated heart failure, serum calcium, magnesium, or potassium levels below the lower limits of normal.

SIRTURO™ has not been studied in patients with ventricular arrhythmias or recent myocardial infarction.

Hepatic-related Adverse Drug Reactions: More hepatic-related adverse drug reactions were reported with the use of SIRTURO™ plus other drugs to treat TB compared to other drugs used to treat TB without the addition of SIRTURO™. Alcohol and other hepatotoxic drugs should be avoided while on SIRTURO™, especially in patients with diminished hepatic reserve. Monitor liver-related laboratory tests. Discontinue SIRTURO™ if aminotransferase elevations are accompanied by total bilirubin elevation >2xULN; aminotransferase elevations are >8xULN; aminotransferase elevations persist beyond 2 weeks.

Drug Interactions:Co-administration of rifamycins (e.g., rifampin, rifapentine and rifabutin) or other strong systemic CYP3A4 inducers should be avoided. Co-administration with strong systemic CYP3A4 inhibitors for more than 14 consecutive days should be avoided. Appropriate clinical monitoring for SIRTURO™-related adverse reactions is recommended.

HIV-TB Co-Infected Patients: There are no clinical data on the combined use in HIV/MDR-TB co-infected patients and only limited clinical data on the use in HIV/MDR-TB co-infected patients who were not receiving antiretroviral therapy.

Treatment Failure: SIRTURO™ should be administered by directly observed therapy. SIRTURO™ should only be administered in combination with at least 3 drugs active against the patient's TB isolate. Non-adherence to the treatment regimen could result in failure or resistance.

Adverse Reactions

The most common adverse drug reactions reported in greater than or equal to 10% of patients treated with SIRTURO™ compared to the placebo treatment group are nausea (38% vs. 32.1%), arthralgia (32.9% vs. 22.2%), headache (27.8% vs. 12.3%) and additional adverse events reported in greater than or equal to 10% of patients are hemoptysis (17.7% vs. 11.1%) and chest pain (11.4% vs. 7.4%).

SIRTURO™ was discovered by researchers at Janssen and is currently under review by three regulatory bodies including the European Medicines Agency (EU), State Food and Drug Administration (China) and Medicines Control Council (South Africa).

About Janssen Therapeutics

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in HIV and other infectious diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Headquartered in Titusville, New Jersey, Janssen Therapeutics, Division of Janssen Products, LP, is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Visit www.JanssenTherapeutics.com for more information and follow us on Twitter at @JanssenUS.

Dr. Reichman is a paid consultant of Janssen.

(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Products, LP and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; increased scrutiny of the health care industry by government agencies; manufacturing difficulties or delays; and product efficacy or safety concerns. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2012. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither Janssen Products, LP nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments).

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